The primary objective of this project is to elucidate the mechanism(s) of selectivity of tumor-specific leads discovered by the NCI in vitro antitumor drug screen. The research strategy focuses upon aspects related both to cellular structure and functions which may contribute to tumor-type selectivity. Currently the project is directed towards elucidation of mechanism(s) of selective cytotoxicity of certain quaternized ellipticines for the brain tumor subpanel which is comprised of tumors of the supporting elements of the brain. These studies are assessing several hypotheses to account for the close correlation between cellular accumulation of 9-methoxy-N2-methylellipticinium acetate (MMEA) and cytotoxicity. These hypotheses include (1) uptake by the monoamine transporter or by a cytochrome P-450 "transport" related protein and (2) preferential metabolism of MMEA by brain tumor and/or non-brain tumor cell lines. Additional investigation into the role of membrane potential as a determinant of both cellular accumulation, intracellular localization and cytotoxicity of this lipophilic cation by brain tumor cell lines is also anticipated.